The brain, different from other organs, exists under particular environment such that it is dipped in cerebrospinal fluid within rigid bodies such as the skull and pachymenix and is one of such organs as showing most active energy metabolism. The oxygen consumption rate of the brain is the highest among all of the organs. Most of energy required for cranial nerves cells are supplied with oxygen and glucose. Since these energy sources are scarcely stored in the brain, they are always supplied from blood. Therefore, mechanism for controlling cerebral blood flow in the cerebral blood vessel itself is well developed in order to stably supply energy source for the brain tissue and to keep the outer environment constant in the cranial nerves cells.
However, when the homeostatic mechanism is damaged in the brain by physical oppression such as cerebrovascular disorders, cerebral tumor or cerebral injury, the cranial nerves cells are exposed to hypoxic condition (cerebral anoxia/cerebral hypoxia) and cannot fulfill the normal function. Such condition of cerebral anoxia increases the production of various toxic active oxygen species. These activated oxygen species peroxidize membrane lipid of the cerebral mitochondria and it results in functional disturbance of the cranial nerves cells and finally a breakdown of the brain cells themselves. This gives such a vicious circle that the functional disturbance of the cranial nerves cells and the breakdown of the brain cells in turn induce severe cerebral anoxia This is the reason why the cerebral anoxia is called a common denominator of most disorders based on cerebral circulatory disturbances [Eur. Neurol., 17 (Supple. 1), 113 (1978)].
Under such circumstances, the present inventors have continuously studied to find compounds having an excellent protective effect against cerebral anoxia and preferably with an inhibitory effect on lipid peroxidation of brain mitochondria. The present inventors have finally succeeded in selection of novel dibenz[b,e]oxepin derivatives of the present invention and completed the present invention.
Prior arts relevant to the present invention include U.S Pat. No 4,144,337 and South African Pat. No. 85/3053.
In the above U.S. Pat. No. 4,144,337, the compounds having the following general formula (A) are disclosed. ##STR2## wherein each of R.sub.1 and R.sub.4, which may be the same or different, is hydrogen, halogen of atomic number from 9 to 35, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, either each of R.sub.2 and R.sub.3 is hydrogen or R.sub.2 and R.sub.3 together are oxygen, either B and D together with the carbon atoms to which they are bound form a benzene ring, or B is sulphur and B and D together with the carbon atoms to which they are bound form a thiophene ring which may be substituted in the position .alpha. to the sulphur atom with halogen of atomic number from 9 to 35 or alkoxy of 1 to 4 carbon atoms, and when B and D together with the carbon atoms to which they are bound form a benzene ring, A is oxygen, sulphur, --CH.sub.2 --O-- or --CH.sub.2 --S-- in either orientation, or a group of formula ##STR3## wherein each of R.sub.5 and R.sub.6, which may be the same or different, is alkyl of 1 to 4 carbon atoms, or when B is sulphur and B and D together with the carbon atoms to which they are bound form a substituted or unsubstituted thiophene ring, A is a group of formula ##STR4## wherein each of R.sub.7 and R.sub.8, which may be the same or different, is hydrogen or alkyl of 1 to 4 carbon atoms and either each of E and F is hydrogen or E and F together form a bond.
Bearing in mind the structure of the compounds of the present invention, which will be fully explained hereinafter, detailed investigation of the very complicated substituents of the general formula (A) indicates that the general formula (A) covers an extremely small part of the compounds of the present invention. However, this U.S. patent does not disclose any example of the dibenz[b,e]oxepin derivatives. Further, although it is disclosed in this U.S. patent that the compounds specifically disclosed therein have psychostimulants and vigilance-increasing effect, these activities are completely different from those of the compounds of the present invention.
The above South African Pat. No. 85/3053 discloses the compounds represented by the following general formula (B). ##STR5## wherein X is hydrogen, halogen, lower alkoxy, lower alkylthio, lower alkylsulfonyl or trifluoromethyl, R is hydrogen, lower alkyl, cinnamyl, lower alkoxycinnamyl, cinnamoyl, lower alkoxycinnamoyl, lower hydroxyalkyl or carbalkoxy, Z is a saturated or unsaturated 2-3 atom chain in which no more than one atom of the chain is other than carbon and which optionally may be substituted with 1 to 2 halogen atoms.
The above general formula (B) contains a part of the compounds of the present invention. However, the South African Patent disclosing the above general formula (B) does not specifically disclose the compounds of the present invention. This South African Patent also discloses that a compound effective as inhibitors of calcium induced-contraction of vascular smooth muscle is useful for treatment of cardiovascular disorders as calcium entry blockers. However, the effect and the use disclosed in this literature are entirely different from those of the present invention.